This invention relates to benzodiazepines having inverse agonist or antagonist properties, and to their therapeutic use.
Benzodiazepines (BZDs) are important therapeutic agents which act on the central nervous system as anxiolytic, hypnotic, and anti convulsant agents (Colotta et al., 31 J. Med. Chem. 1, 1988). They are also used as sedatives and muscle relaxants. One example is diazepam, the structure of which is shown in the FIGURE. The physiological effect of BZDs is dose dependent. For example, at low doses diazepam is anxiolytic and anti convulsant, and at higher doses it acts as a sedative and muscle relaxant.
BZDs interact with neuronal membrane proteins, termed BZD receptors, which may be located in GABA-ergic synapses and are classified as peripheral, neuronal, and central receptors. Referring to the FIGURE, examples of some compounds with affinity for these BZD receptors are shown. These compounds have diverse structures and give rise to different physiological effects. For example, the .beta.-carbolines, ZK91296, ZK93426 and FG7142 are a partial agonist, antagonist, and partial inverse-agonist, respectively.
As used herein, an agonist refers to a compound having a similar physiological activity to a BZD, which produces a maximal response in a tissue even when it occupies less than all of the BZD receptor sites. A partial agonist is a compound having low efficacy, and producing a physiological response less than the tissue maximum, even when it occupies all available BZD receptor sites. Other examples of partial agonists include CL218872 and CGS9896 (the FIGURE) An inverse-agonist is a compound which produces the opposite physiological effect of an agonist; a partial inverse- agonist has some of the properties of an inverse-agonist. Examples of inverse-agonists include .beta.-carboline derivatives such as 8CM, .beta.CE and Ro 15-4513 (the FIGURE); examples of partial inverse agonists are 3-ethoxy-.beta.-carboline and ZK90886. An antagonist is a compound which reduces or eliminates the physiological activity of an agonist or inverse-agonist on a tissue, and which has little intrinsic activity on the tissue by itself. Another example of an antagonist is Ro 15-1788 (the FIGURE). Partial agonists may also have some antagonist-like properties.
Dua et al. (63 J. Indian. Chem. Soc. 425, 1986) demonstrated that introduction of hydroxy, alkoxy, and carboxy groups at the 3-position of 1, 4 benzodiazepines produces anxiolytic compounds, i.e., BZD agonists. Introduction of a morpholino group or methoxy benzoyloxy group at this position also produces compounds with appreciable anxiolytic activity, but devoid of CNS depression activity, indicative of their BZD antagonistic nature. Id.
Boltze et al. U.S. Pat. No. 4,647,560, hereby incorporated by reference, describes BZDs, derived from 1,4 benzodiazepines, useful for treatment of cerebral disorders caused by old age, as well as disorders of learning and memory. These compounds have substitutions at the 3-position. including unsaturated ring structures. These compounds have no affinity for BZD receptors and show no anxiolytic activity, but exhibit potent phychotropic activity in animals.